Acyl-coenzyme A cholesterol acyltransferase (ACAT) is an enzyme which catalyzes synthesis of cholesterol esters from cholesterol and plays an important role in metabolism and absorption of cholesterol through the digestive tract. Recent studies have clarified that when activity of ACAT present in the small intestine and liver is inhibited, elevation of blood cholesterol can be effectively prevented. Thus, extensive research efforts have been made on ACAT inhibitors.
Having focused on a specific type of ACAT that is present in the vascular wall, the applicants previously studied a substance which selectively inhibits the ACAT, and found that, among azole compounds having a cyclic diamine structure, cyclic diamine derivatives represented by the following formula (4′):
(wherein A is NH, O, or S; each of Wa to Wd is CH, or one of Wa to Wd is N; Ra is lower alkylthio group, lower alkoxy group or halo lower alkoxy group, or lower alkoxy lower alkoxy group; Rb, Rc, and Rd are each a hydrogen atom, a halogen atom, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, halo lower alkyl group, halo lower alkoxy group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy group, hydroxy lower alkyl group, hydroxy lower alkoxy group, lower alkylcarbonyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, nitro group, or cyano group; m is an integer of 1 or 2; and n is an integer of 1 to 6) and salts thereof are useful therapeutic drugs for hyperlipidemia and arteriosclerosis by virtue of less side effect, excellent water-solubility, and oral absorption. They filed an international patent application on the basis of these findings (Patent Document 1).
The mentioned patent application discloses a method for producing a cyclic diamine derivative (4′) through the below-described production method 1 (Example 24) and production method 2 (Example 88). The application also discloses production of a compound (e) via compounds (a) to (c) in accordance with the method described in Patent Document 2. However, the methods disclosed therein have the following problems. That is, since chlorine atoms of a starting compound (a) are highly reactive, when reaction for introducing lower alkylthio groups is carried out in methanol, compounds having methoxy group at the 4- (or 2-) position are produced as byproducts. Moreover, a subsequent reaction for reducing the nitro group of nitropyridine (b) having introduced lower alkylthio groups gives an amine compound (c) accompanied with byproducts without alkylthio group(s). This leads to a further problem of the presence of impurities that are difficult to remove from compound (e).
On the other hands, production method 2 involves the following problems. That is, in reaction steps for producing a target compound (p) starting from compound (m) via intermediate (n) and reaction with (o), compound (n) is unstable, permitting formation of an aziridinium intermediate, which raises an issue of byproducts.
In manufacture of a drug substance, in addition to stable supply, reasonable and efficient control of impurities in each production step is required. The presence of byproducts ultimately leads to the necessity of control of the impurity profile of a pharmaceutical substance.
Patent Document 1: Pamphlet of International Publication WO 98/54153Patent Document 2: Japanese Patent Publication (kokoku) No. 25974/1996